Declining incidence of cerebral palsy in South Korea

Presuming that the incidence of cerebral palsy (CP) in Korea is decreasing due to medical advances, we analyzed the trends and risk factors of CP in changing circumstances. We identified all women who delivered a singleton between 2007 and 2015 using the Korea National Health Insurance (KNHI). Information on pregnancy and birth was obtained by linking the KNHI claims database and data from the national health-screening program for infants and children. The 4-years incidence of CP decreased significantly from 4.77 to 2.52 per 1000 babies during the study period. The multivariate analysis revealed that the risk of developing CP was 29.5 times higher in preterm infants born before 28 weeks of gestational age, 24.5 times higher in infants born between 28 and 34 weeks, and 4.5 times higher in infants born between 34 and 36 weeks, compared to full-term appropriate for age (2.5 ~ 4 kg of body weight) infants. 5.6 times higher in those with birth weight < 2500 g, and 3.8 times higher in pregnancies with polyhydramnios. Additionally, respiratory distress syndrome increased the risk of developing CP by 2.04 times, while necrotizing enterocolitis was associated with a 2.80-fold increased risk of CP. In Korea, the incidence of CP in singleton decreased from 2007 to 2015. We need to continue to focus on developing medical technologies for the early detection of high-risk neonates and minimizing brain damage to reduce the incidence rate of CP effectively.

www.nature.com/scientificreports/ included in our study. To ensure the reliability and validity of our analysis, we excluded twin babies from the study sample as they could result in duplicate data from the same mothers. Moreover, since twin births represent only a small proportion of all births, their exclusion allowed for a more representative sample of the general population. Detailed information, such as medical illness, delivery mode, pregnancy complications, and single or multiple pregnancies, was confirmed using data from the KNHI claims and the national health-screening program for infants and children.
CP case definition. We assumed an initial diagnosis of CP for early treatment if a diagnostic code had been registered. In addition, we defined cases of cerebral palsy using the Tenth Revision of the International Classification of Diseases: spastic quadriplegic CP (G80.0), spastic diplegic CP (G80.1), spastic hemiplegic CP (G80.2), dyskinetic CP (G80.3), ataxic CP (G80.4), other CP (G80.8), CP, unspecified (G80.9). Hereditary spastic paraplegia (G11.4) was excluded. Upon diagnosis of CP, the number of people was summed based on the child's birth year. The observational period was at least four years after birth.
Incidence of cerebral palsy. The yearly incidence of CP per 1000 live births was calculated using the total number of infants born during the study year as the denominator and the number of infants diagnosed with CP during subsequent follow-up as the numerator.
Risk variables.
Statistical analysis. Statistical analysis was performed using SPSS software version 12.0 (SPSS Inc., Chicago, IL, USA). The Student's t-test was used to compare continuous variables between groups. The categorical variables were compared using the χ2 test. We compared temporal trends by using the χ2 test. Multivariate logistic regression analysis was used to estimate the adjusted odds ratio (OR) and 95% confidence interval (CI). All P-values were two-sided and were considered statistically significant if 0.050 or less.

Ethics approval and consent to participate. The institutional review board of the Korea University
Guro Hospital approved the study (2020GR0468) and granted a waiver for informed consent because of its retrospective nature.

Results
Trends in vaginal and cesarean births by year. As shown in Fig. 1 Comparison of the study population. According to a combined analysis of maternal and their babies' records, the frequency of advanced maternal age, hypertension, and diabetes before and during pregnancy, diabetes mellitus before pregnancy, cesarean delivery, gestational hypertension, gestational diabetes mellitus requiring insulin treatment, chorioamnionitis, premature rupture of membrane, oligo-and polyhydramnios, preterm birth, low birth weight, male sex, and large for gestational age was higher in the group diagnosed with CP than in the controls (Table 1).
Risk factors for developing cerebral palsy. In Table 2 www.nature.com/scientificreports/ The annual incidence rate of risk factors. Figure 3 presents the annual incidence rate of cerebral palsy's three major risk factors. Our results demonstrate a statistically significant reduction in the incidence of preterm birth, from 3.23 to 1.91% (p = 0.015), as well as a slight increase in the proportion of full-term small-forgestational-age, from 1.85 to 1.91% (p = 0.032). On the other hand, we observed no significant variation in the occurrence rate of polyhydramnios over the study period.

Discussion
Our data revealed that the incidence of CP per 1000 live births declined significantly from 4.77 to 2.52 babies among all live single births between 2007 and 2015. The likelihood of developing CP is 4.54-29.49 times higher in preterm babies than in full-term babies of the appropriate weight. Additionally, full-term babies who are smallfor-gestational-age (body weight <2.5kg) have a 5.39 times higher risk of developing CP, and pregnancies with polyhydramnios have a 3.81 times higher risk of CP. Neonatal conditions, such as respiratory distress syndrome and necrotizing enterocolitis, have increased the risk of developing CP by 2.04-fold and 2.80-fold, respectively.     well-known as a risk factor for CP 8,9 . The immature brain cannot effectively maintain a blood supply because there are fewer collateral vessels or anastomoses around the peripheral blood vessels and immature walls. The vessels cannot compensate for hypoxic-ischemic damage to limited vasodilation capacity 10 . Thus, various attempts have been made to prevent preterm birth; 17α-hydroxyprogesterone caproate may help prevent recurrent preterm birth [11][12][13] . Furthermore, vaginal progesterone prevents premature birth of mothers with short cervixes and improves neonatal outcomes [14][15][16] . Overall, progesterone administration lowered the rate of preterm births by approximately 50% 15,17 . Cervical pessary use or cervical cerclage prevents repeated preterm births in high-risk women with a short cervix 18 . Despite medical advances, the rate of preterm births increased from 2.9% (1997-1999) to 4.5% (2011-2013) 19 and from 3.31% (1997-1998) to 6.44% (2013-2014) 20 in Korea. The increase in twin births is thought to have contributed to the rise in preterm births. As shown in Fig. 3, singleton's incidence of preterm birth slightly decreased between 2007 and 2015 (p = 0.015) in our study.
Fetal growth restriction. The association between the development of CP and fetal growth restriction is well known 21 . Fetal growth restriction has been reported as a more critical risk factor for CP than fetal inflammation and birth asphyxia combined 22 . In our study, based on the limitations of the available data, an alternative approach was taken to analyze the risk of cerebral palsy associated with growth abnormalities. Since accurate gestational age data was unavailable from the claim data, term babies were categorized based on their birth weight into three groups: those weighing less than 2.5kg, those weighing between 2.5kg and 4kg, and those weighing 4kg or more. Despite the limitations, this method allowed for a more detailed investigation of the potential risk factors linked to cerebral palsy in infants with growth abnormalities. Our results showed that fullterm babies who are small-for-gestational-age (body weight <2.5kg) have a 5.39 times higher risk of developing CP compared to full-term babies of appropriate weight, concordant with the previous studies.
Polyhydramnios. In our study, polyhydramnios increased the risk of CP by 3.81 times. Polyhydramnios has also been associated with increased perinatal morbidity and mortality risk, such as preterm birth, aneuploidy, cesarean section, fetal anomalies, and perinatal and postnatal mortality 23,24 . Even when the results of a detailed ultrasound examination of the fetus were normal, polyhydramnios doubled the risk of genetic syndromes, neurologic disorders, and fetal malformations diagnosed after birth 25 . The incidence of polyhydramnios did not change over the study period (Fig. 3, p = 0.367).
Postnatal risks. Our study found that respiratory distress syndrome and necrotizing enterocolitis were associated with a 2.04-fold and 2.80-fold increased risk of developing CP, respectively. Our study's results align with the prior studies, as it reported that moderately late and late preterm infants (32-36 weeks) who experienced respiratory distress syndrome had a two times higher incidence of CP than those without respiratory distress syndrome at the same gestational weeks 26 . Moreover, a meta-analysis demonstrated a 1.59-fold increased risk of CP in neonates with necrotizing enterocolitis, possibly due to heightened exposure to proinflammatory cytokines and the associated risk of sepsis 27 . In addition, it is important to note that although not included in our study data, the advancements in various medical technologies aimed at protecting the neonatal brain may have contributed to a reduction in the incidence rate of CP. First, magnesium sulfate (MgSO 4 ) stabilizes blood pressure, reduces vasoconstriction in the cerebral arteries, and restores circulation in preterm neonates 28,29 . Treatment with MgSO 4 in preterm labor may lower the risk of CP [30][31][32] . The proportion of moderate to severe CP decreased significantly in babies born in women with preterm birth who were treated with magnesium (relative risk, 0.55; 95% CI 0.32-0.95) 31 ; several meta-analyses also support this result [33][34][35] . Second, the prenatal administration of corticosteroids for fetal lung maturity may  Figure 3. Annual trends in risk factor occurrence. There was a slight decrease in the percentage of preterm births, whereas the proportion of full-term small-for-gestational-age increased slightly. However, there was no significant change in the frequency of polyhydramnios throughout the study period. www.nature.com/scientificreports/ reduce the occurrence of CP 36 . Finally, brain or whole-body cooling has become standard management for neuroprotection in newborns with birth asphyxia 37,38 . Through various efforts, including improvements in prenatal and neonatal care, Korea has decreased the infant mortality rate from 4.7 in 2004 to 3.0 in 2014 39 . Moreover, our study revealed a continued decline in the incidence of CP in Korea.

Limitations.
In this study, we assumed that the registration of a diagnostic code indicates an initial diagnosis of CP. However, it is important to acknowledge that diagnosing CP can be challenging and may change as more information is gathered or the child develops. Children with mild CP may not be diagnosed until later in life, as their symptoms may not be as apparent during early childhood. Therefore, our study may include cases where a tentative diagnosis was made to receive early physical therapy. In some healthcare settings, it is common practice for healthcare professionals to diagnose a child with CP for this purpose tentatively. However, it is important to note that including such cases may have contributed to potential inaccuracies in our findings, which should be considered when interpreting our results. We also acknowledge the limitations of relying solely on diagnostic codes for diagnosing CP in our study. Using administrative data in research may result in potential inaccuracies due to the lack of clinical data in the analysis, a recognized limitation commonly encountered in studies utilizing administrative data. Given the absence of accurate gestational age data in the medical claim database, we categorized term babies based on birth weight and analyzed them to alternatively assess the risk of cerebral palsy associated with growth abnormalities.
While our study successfully linked birth records of infants born in the hospital to their respective mothers, it is essential to note that our study's scope is limited to infants born within the hospital. Thus, our study did not include roughly 1.5% of births outside the hospital. Furthermore, a small number of individuals who may have emigrated or died at some point after birth cannot verify their status within our research data. Finally, while a child can be diagnosed with CP if a triggering event occurs before the affected function fully develops 1 , our study was unable to identify perinatal risk factors of CP such as birth asphyxia, neonatal sepsis, or respiratory distress syndrome, as well as early infantile risks such as encephalitis or head trauma.

Conclusion
In Korea, the incidence of CP decreased from 2007 to 2015. Based on our findings and analysis, we can infer that the efforts to protect the brain of neonates before and after birth through advanced technologies have effectively reduced the incidence rate of CP. Therefore, we need to continue to focus on developing medical technologies for the early detection of high-risk neonates and minimizing brain damage to reduce the incidence rate of CP effectively.

Data availability
The datasets used or analyzed during the current study are available from the corresponding author upon reasonable request.